Investigating immune cell “macrophage” driven drug resistance in Acute Myeloid Leukaemia

Acute Myeloid Leukaemia (AML) is one of the most pressing unmet clinical needs in the blood/haematology field, with 131 individuals in Tayside and Fyfe, recorded between 2015-2019 to have AML (https://publichealthscotland.scot/media/7784/summarised-cancer-incidence-leukaemias.xls ). In the UK it is the second most common blood cancer in adults, and for the majority of AML patient’s survival is between 20-30%, with little improvement in these figures observed in the last decade. Cancer drug resistance is a major contributing factor towards poor survival in AML patients, which is significantly influenced by cells residing in the bone marrow AML cells have the potential to interact with immune cells termed “macrophages”, with a well-established role for macrophages promoting drug resistance in blood cancers, such as Multiple Myeloma. Macrophages can be divided into two main types M1 “classical” and M2 “alternatively activated” macrophages. M1 macrophages possess pro-cancer properties, promoting the killing effects of cancer therapy, and express the proteins CD86 and CD80. On the other hand, M2 macrophages, have pro-cancer activities, that drive resistance to cancer drugs, and express the proteins CD163 and CD206. M2 macrophages are present in high numbers in the bone marrow of blood cancer patients with AML, and multiple myeloma (MM). In MM These macrophages are known to contribute towards therapy resistance, through direct physical contact with blood cancer cells and/or factors released by macrophages that aid in blood cancer cell survival. It is important that we identify; 1. The factor(s)/mechanism(s) by which AML cells re-instruct macrophages towards a leukaemia-supporting type, and 2. The mechanisms by which these leukaemia-supporting macrophages then drive therapy resistance in blood cancers, as very little is known about how these disease processes occur. This work will answer several questions on how this happens and the research is important in order to explore the potential of new drug treatments for blood cancers, which in the long-term is expected to lead to improvements in clinical outcomes for blood cancer patients.